Medical preparation containing arsenic and process for making the same



Patented Oct. 4, 1927.

UNITED S I IWAN OSTROMISLENSKY, OF LOCUST POINT, NEW JERSEY, ASSIGNOR TO OSTRO PROD- UCTS CORPORATION OF AMERICA, JERSEY CITY, NEW JERSEY, A CORPORATION or new JERSEY.

MEDICAL PREPARATION CONTAINING ARSENIC AND TROCESS FOR MAKING THE SAME.

No Drawing.

This invention relates to improvements in medical preparations containing arsenic and processes for making the same. It relates more particularly to such-preparations having. the therapeutic'properties of the salvarsan class, and processes for making the same. Salv'arsan, as is well known, is dioxydiaminoarsinobenzol dichlorhydrate.

It is considered a postulate that every medical preparation and particularly medical preparations containing arsenic should be prescribed in minimal doses just suflicient to destroy the disease producing organisms in a patients body while producing the ,desired therapeutic effect. Salvarsan and like materials are prescribed in doses which contain from 0.09 to 0.18 grain or more of arsenic. With doses such as these the patient is apt to become a depot of arsenic. That is by the present methods of using salvarsan, for example in the treatment of syphilis, the gradual accumulation of arsenic in the treated person is inevitable. This accumulation leads to prolonged catarrhal conditions of the liver and hepatic ways and this catarrhal condition is apt to give rise to other more serious hepatic troubles in accordance with the findings of- Prof. Dr. Arndt, Dr. Max Joseph and others.

The principal object of the present invention accordingly ,is to rovide a series of medical preparations which shall not be apt to'decomposeupon standing and which shall Application filed July 22,

1922'. Serial No. 576,883.

have the same or a greater-therapeutic effect than salvarsan and similar materials in the treatment of diseases for which these substances are indicated, when prescribed in doses containing much smaller quantities of arsenic than present in salvarsanand the like. Another object of the invention is to provide a simple inexpensive process for obtaining such medicinal preparations. 4

The invention accordingly consists in a medicinal preparation which comprises an arsenic-oxygen compound, containing AsO, As(OH)-; and its salts or the salts or anhydrid'e. of arsenious acid in solution with a protective colloid, such as gum-arabic, lysalbic acid, protalbic acid, gelatine, albumin, peptone, casein, blood serums and others. There may also be added to this preparation substances causing the solution to become isotonic with blood, if desired. Such isontonic substances include saccharine, glucose, Ringers or Locks solutions, sodium chloride and cane sugar.

In examining the hitherto unexplained process of the complicated transformations of salvarsan, neosa'lvarsan (606, 914) etc. which, in themselves, occur at normal temperatures, without the. presence of any catalizers or sensitizers or any other means of forcing the results, it has been discovered that a new reaction occurs, which can be expressed as follows:

It has also been observedthat the known reactionof decomposition of the aromatic arsenious oxides (for example substance (1) 70 in the above equation) b which are formed arsenious anhydride an the corresponding primary arsine, thus In this adsorption can take place at normal temperature by itself under conditions approaching those found in a living body. It will be observed in accordance with the first equation that free arsenic is formed which as pointed out above inevitably accumulates in the patients body.

A The reactions above indicated requlre an appreciable time for completion. The first human or animalat v salvarsan is selec-' the usual doses of sites. .When suc tively fixed by pallida sp'irochaeta of Sch'auon microscopic slides of various syphilitic materials. Bacteria and blood counts (Leucocytes, red corpuscles, etc.) of such slides remain unafl'ected. Salvarsan fixed by the spirochaeta retains for a long time its original chemical properties. For instance,

black color of colloidal silver appearswith silver nitrate only on suchportions of the slide as have adsorbed salvar'san in an'unchanged form. Therefore we can observe directly with our own eyes the selective, purely physical union of salvarsan particleswi th the plasm of Schaudins spirochaet-a.

This first andhighly characteristic phase of mutual interaction etween salvarsan (or other colloid) and the disease producing bacteria must without doubt be considered .a physical process. The second phase consists of the decomposition of salvarsan as above described first, with the formation of the corresponding arsenious oxide and finally,

the formation of the anhvdride as well as of the corresponding salt of arsenious acid. These bactericidal products of auto-decomposition of salvarsan and its allied preparations form directl in the plasm of the paraproducts are sufliciently accumulated, they destroy the parasites.

'When apatient is. treatedwith one of the preparations included in the present invention the colloid is selectively absorbed by the disease producin parasite to which the arsenious oxide an ydride or acid is simultaneously transferred. Thus the bactericidal matter is transferred instantly to the para site plasm in a sufiicient quantity to destroy the parasite.

The following are examples of preparations which have been employed with excellent results, in accordance with the presentinvention,.in the treatment of typhus recurrens, syphilis, febris intermittens tertiana,

sleeping sickness, carbuncles, frambes ie, anthrax, nervous-disorders and other diseases in which arsenic is applicable: Q

Examples.

1. 0.56 gm's. of arsenious anhydride and 900 061 of water are placedin a round bottom glass retort fitted with a return condenser.

. The mixture-is heated over an open flame and allowed to boil for 40-60 minutes. A

perfectly clear solution is obtained and to it 1. added a solution ofv 1.5 gins. of gumarabic in 100 cc. of water. To maintain the solution isotonio'with blood, there is added to the general mixture 10 gms. of saccharose or ad glucose, or 8.5 to 9 gms. of sodium c loride. Salts of Ringers or Locks solutions and others may also be used for the same purpose. The resultant solution is filtered, if necessary, and upon preliminary sterilization is distributed in phials.

The proper dose for treatingsyphilis, malaria or remittent typhus is 10-20 cc. This dose contains only 0.00420.0084: gms. of arsenic.

, Example 2.-The curative solution is obtained identically as in Example 1, but the amount of gum-arabic added to the anhye dride solution is reduced from 1.5 gms. to 0.45 gins, which also may be replaced by 0.45- gms. gelatine' or by a mixture of 0.75 gms. of gum-arabic and 0.75 gms. of glelatline. The mixture is then treated as in Example 3. To a fresh solution of arsenious anhydride (1 m.) and cane sugar (10 gms.) in 1000 cc. 0 water, are'added, at normal temperature (15 C.), 3-6 cc. of human or horse blood serum. The solution must naturally be kept under sterile conditions. The curative dose of the preparation therapeutically equivalent to the normal doses of salvarsan (0.3-0.6 guns. for 606; 0.45 0.90 gins. for 914 etc.) is at most equal to 10 cc which contain only 0.0076 gms. of arsenic. 1

Example 4. 1 gm. of AS203, 2.6 guns. of gelatine and 10 gms. of cane sugar (or; 8.5 gins. of NaCl) are dissolved simultaneously or consecutively, in any order, in 1000 cc.

of pure water at boiling temperature. The.

curative dose. of the resulting-solution therapeutically equivalent to normal doses of salvarsan preparations contains only 0.003- 0 006 gms. of arsenic.

Example 5. 0.5 gm. of pa'raoxyphenylarsenious oxide and 1-2 gins. of gelatine are dissolved simultaneously or in any consecutive order in 1000 cc. of water after the latter has been rendered alkaline by the addition of a very slight amount of sodium hydro'xid'e. The proper dose of the resulting Inn hypo-isotonic solution which is equivalent therapeutically to the normally prescribed dose of salvarsan preparations equals approximately 5 cc., which contain only 0.0025 gms. of arsenious oxide or 0.001 gm. of arsenic, according to the formula.

Example 6. The solution is prepared identically as in Ex. 5 but the gelatine is replacedby 1 or 2 gms.' of gum-arabic or a mixture of l-gm. of the latter and one gram of peptone, or-a mixture-of 0.5 g1n. gelatine, 0.5 gm. gum-arabic and 1 cc. sterilized blood serunnetc.

Note: In order to render the solutions prepared according to Exs. 5 and 6 isotonic normal temperature,

with. human blood, proper additions may be made of sodium chloride, salts of Ringer or Lock solutions, cane sugar, glucose or tate results, which is filtered, dried etc. is

for purification in pure acetone, and again precipitated by ether. Upon dryin the second precipitate in a desiccator, a ye lowish powder is obtained which contains practically the full 10% of the original arsenious oxide. The powder gives clear and fairly permanent solutions in water, without any residue, precipitate or turbidity. The correct dose of that preparation which is therapeutically equivalent to the normal doses (0.3-0.6 gm.) of German salvarsan equals on the average-0.075 gmL, The dose is taken from a. solution containing one gram of the powder resulting from the above procedure dissolved in 20 cc.-500 cc. of water.

It will be observed here that salvarsan is employed as a protective colloid replacing gum-arabic, gelatine, etc.

Example 9. A fairly strong current of air is passed in the dark through an acidulated (by HCl) solution of 100 gms. of salvarsan in 1000 cc. of moisture free, chemically pure, methylalcohol. The process is continued for 6 hrs. To accelerate the reaction, fuming nitric acid of 1.41.5 specific gravity may be added up to 3 cc. to act as an oxidizin agent. At the end of the process the solution is poured into 10 liters of dry ether and the precipitate is filtered and further treated just as in the previous example.

Example 10. Alkaline solution of 100 gms. of German salvarsan in 10 liters of water is allowed to stand, open to air and at for 4-5 days. Then the solution is neutralized by very dilute hydrochloric acid. This results in the precipitation of dioxydiaminoarsenobenzol. The precipitate is separated by centrifuging, dissolved in hypochlorous acid in the presence of alcohol and precipitated by ethyl ether. After the precipitate is treated according to the usual procedure and is dried in a desicagain dissolved methyl alcohol, free from 'cator over parafline and sulphuric acid, a

yellow brownish powdery substance is obtained, which contains from 8 to 15% paraoxymetaminophenylarsenious oxide.

Example 11. I A solution of 1 kilo of 914 (German salvarsan or Russian navarsol) having the constitution (iPhOSONa in 2 liters of distilled'water is allowed to stand for 26 hours in an open vessel in the dark at normal temperature. The resulting product is then poured into 25 liters of 98% ethyl alcohol. A precipitate is formed which consists of the corresponding arsenious oxide HOQ-Astl oAsQon Hm NH (lHaOSONa It is filtered, washed, pressed and dried to a constant weight, according to usual procedure. The. resulting product contains from 8 to 15% of the corresponding arsenious oxide. The dose of the material so prepared is from 0.12 grams where 8% of the oxide is present to 0.06 ams where 15% of the oxide is present. he dose is administered preferably in water solution dissolved in 20500 cc. of' distilled water.

Neosalvarsan or Russian navarsol also acts here as a protective colloid.

Example 12. To 40 cc. of 0.1% solution of As O prepared by boiling in a glass 1e tort with a return condenser and cooled to normal temperature, is added 'a solution of 0.9 gms. of Russian neosalvarsan (i. e. navarsol, containing 10% As) in 80 cc. of distilled water. The resulting product is arsenious acid physically bound, or adsorbed. by neosalvarsan as a protective colloid. The medical dose of this product which is therapeutically equivalent to normally prescribed quantities of neosalvarsan is approximately 10 cc. This quantity contains, therefore only 0.0075 gm. of As in the f orm of neosalvarsan and 0.0025 gm. of As in the form of adsorbed arsenious acid, or a total of 0.01 gm; of As as against 0.135 gm. of As which 1s usually given to patients in single 1 n ections of German neosalvarsan.

Example 13. A common solutionbi 5 gms. of arsenious anhydride, 2.5-3 gms. pure solid sodium hydroxide and 5-15 gms. gum-arabic (or an equal quantity of gelatine) in 125 cc. of water is added to 625 cc. of moisture free, chemically pure, methyl alcohol. To this mixture is gradually added, while stirring, about 200 cc. of dry sulphuric ether." A precipitate is formed which consists of sodium arsenite adsorbed by, or physically bound to, gum-arabic orgelatine or whatever other substance was used in their stead. The precipitate is filtered under pressure, washed carefully with dry ether, pressed out and finally dried in a desiccator to a constant weight. It is recommended that once or twice during the drying of the final product it be pulverized into a tine powder by means of a porcelain pestle and mortar.

Example 14. Boil'for one hour 1.2 gms. of'arsenious anhydride with 100 cc. distilled water in a retort with a return condenser. Cool down the solution by water to 25 C. while shaking carefully. To a cc. of the so obtained clear liquid add and dissolve by shaking 1.8 gms. of Russian neosalvarsan (navarsol), which usually contains only,10% of arsenic. After 5-10 minutes pour the solution into 35 cc. of chemically pure moisture-freemethyl alcohol. The precipitate which forms after the last operation is filtered under suction through a Buchner funnel, washed first with alcohol and then with ether, well pressed out and finally dried in a desiccator over parafline and sulphuric acid. No vacuum is required for the drying. The resulting product is a fine and, naturally, amorphous powder. The coloring is of a not quite clear yellowish tint.

0.2 gm. of the above preparation, treated by Lemanns process, required, in a return titration of the separated free iodine, 14 cc. of 0.1 N solution of Na S O Consequently, the prepared substance contained arsenious anhydride and, possibly free arsenious acid, adsorbed by the neosalvarsan as a protective colloid. The preparation dissolves readily and'completely in water giving permanent perfectly clear solutions of a slightly yellow tint.

The peculiar physical condition of the mentioned organic arsenious oxides or the anhydride of arsenious acid etc. when adsorbed by colloids such as gum-arable, gelatine neosalvarsan, Russian narvarsol, sal- Varsan, 606, 914, is evidenced by a number of properties which they do not possess at all in their free chemically pure state. Thus the substance-free, chemically pure, paraoxymetaminophenylarsenious oxide given in the last example, as is well-known, is not soluble in Water, hydrochloric acid etc., while the arsenious oxide adsorbed by the salvarsan gives clear solutions in wa ter. When such solutions are accurately neutralized, or are treated with such reagents adapted to separate or precipitate dioxydiaminoarsenobenzol, or the acid or alkaline "salts ofthe latter, this arsenious oxide is simultaneously also separated from the solution.

As a proof of the protective action of salvarsan it is also to be noted that pure paraoxymetaminophenylarsenious oxide is 20 times more toxic than salvarsan but when, as in the above example, this arsenious oxide is adsorbed by salvarsan the toxicity of salvarsan and combinations of salvarsan and this arsenious oxide have substantially equal toxicity.

The preparations listed above, it will be understood, are simply examples of a large number-of compositions employing the substances therein noted and similar substances falling within the scope of the invention. Other arsenic-oxygen compounds and colloids than those set forth may be employed.

In general, by intravenous injection of paraoxymetaminophenylarsenious oxide physically bound with salvarsan as a protec- /tive colloid, a quantity of arsenic which is given the patient by a single injection of 606 or 914 can be reduced from 0.09-0.18 grams to 00045-00090 grams, andeven less. With the use of the new preparation neither the character of the treatment nor its intensity is changed and the usual medical effect is produced just as rapidly and is maintained -for the same length of time as when salvarsan alone is used without causing the patient to become a depot for arsenic.

Experiments have also shown in accordance with the invention that the same results as above are obtained by the use of .neosalvarsan or Russian navarsol with its corresponding arsenious oxide.

In treating typhus recurens, when using for intravenous injection a water solution of arsenious anhydride adsorbed by a small quantity of gum-arabic or gelatine, it is possible to reducethe quantity of arsenic required for obtaining terapium magnum sterilisans, almost 16 times, i. e. down to 0.0560.0080 grams, instead of the 0.09- 0.18 gins. usually applied in the form of salvarsan in such cases/ After such injections of As fl just as after the use of salvarsamthe attacks of typhus recurens cease almost immediately, or at most in the course of 3 to 12 hours and relapses do not occur at all.

Similar results have been obtained in accordance with the present invention in the treatment of malaric (febris intermittens tertiana) as well as of syphilis. In the case of thelatter it has been observed that with a very small dose of arsenious anhydride in adsorption with gum-arabic, not only do the external manifestations of syphilis show a rapid tendency to disappear but also as with salvarsan treatment, the patients Wassermann reaction is changed from positive to negative.

Parallel clinical experiments in which arsenious acid was introduced as such without a protective colloid in one series of experiments and with a protective colloid as hereinset' forth in another series of experiments show that the characteristic medical properties of arsenious acid adsorbed by colloids are absent in the chemically pure reagent. On the contrary, intravenous injection of water solutions of chemically pure arsenious anhydride in the same doses as arsenious anhydride adsorbed by colloids sometimes causes sharp temperature reactions in the patient, but no appreciable therapeutic effect has been observed.

It will be observed that combinations such as those set forth in the examples may be made at ordinary or elevated temperatures.

Instead of the arsenious oxide compounds set forth in the examples pslienyl arsenious oxide may be employed. eta and ortho oxyphenylarsenious oxide may also be employed.

It will thus be seen that effective inexpensive simple medicinal preparations are provided in accordance with the invention adapted for use when arsenic compounds are indicated therapeutically, but .which avoid accumulation of arsenic in the patient; and that simple processes for the manufacture of these preparations are also described. The term organic arsenious oxide as used herein refers to organic compounds containing the ASC group.

As many apparently widely different embodiments of the invention may be made without departing from the spirit thereof, it will be understood that I do not intend to limit myself to the specific embodiment herein set forth except as indicated in the appended claims.

Having thus described my invention, what I I claim and desire to protect by Letters Patquantity of a dose,

cut is:

1. A composition useful for the treatment of sy hilis, and diseases yielding to treat- 'ment y arsenic, comprising an organic arsenious oxide havin by itself a high toxicity when present in t e human body in the quantity of a dose and a protective colloid, said toxicity being reduced by said colloid to permit intravenous or other introduction into the body.

2. A composition of syphilis, and diseases'yielding to treatment by arsenic, comprising anorganic arsenious oxide having by itself a high toxicity when present in the human body in the a protective colloid, said toxicity being reduced by said colloid to permit intraveneous or other introduction into the body, and a substance isotonic with respect to blood.

' 3. A composition useful for the treatment of syphilis, and diseases yielding to treat-. ment by arsenic, com rising an orgamc arsenious oxide havin y'itself a high toxicity when resent in t e human body the quantity 0 a dose, gum-arable, said toxicity useful for the treatment being reduced by said gum-arabic' to permit intravenous or other introduction into the body, and glucose adapted to cause the compound to become isotonic with respect to blood. v v

. 4. A composition useful forthe treatment of syphilis, and diseases yielding to treatment by arsenic,

phenylarsenious oxide and a protective colloid, the toxicity of said paraoxyphenylarsenious oxide being reduced by said colloid to permit intraveneous or other introduction.

which comprises dissolving an organic ar-' senious oxide having by itself a high toxicity when present in the human body in the quantity of a dose and reducing the toxicity by combining therewith an organic protective colloid.

7. A process for preparing a composition useful for the treatment of syphilis'and diseases yielding to treatment by arsenic which comprises dissolvin an organic arsenious oxide having by itse f a high toxicity-when present in the human body in the quantity of a dose and reducing the toxicity by combining therewith a quantity of gum-arabic.

8. .A: composition useful in diseases yielding to treatment by arsenic, comprisi ng an aromatic arsenious oxide and a protective colloid, the toxicity of said aromatic arsenious oxide being reduced by said colloid to permit intravenous or other introduction into the body.

v9. A composition useful in disease yielding to treatmentby arsenic, comprisingan group and'a protective colloid, the toxicity of said arsenious oxide containin the phenyl group being reduced by said co oid to permit intravenous or other introduction into thebody. H I

Signed at New York, New York, this 21st day of July, 1922.

IW AN OSTROMISLENSKY.

less. quantity of arsenic comprising paraoxyaromaticarsenious oxide containing-a phenyl 

